INTRODUCTION

The term myeloma kidney or myeloma cast nephropathy refers to a disorder in which monoclonal urinary immunoglobulin light chains (Bence Jones proteins) lead to acute or chronic renal failure [1,2]. (See "Types of renal disease in multiple myeloma".) Light chains have a molecular weight of approximately 22,000. They are freely filtered across the glomerulus and then largely reabsorbed by the proximal tubular cells. The normal rate of light chain excretion is less than 30 mg/day. However, reabsorptive capacity can be exceeded due to overproduction in multiple myeloma, resulting in an increase in light chain excretion that can range from 100 mg to more than 20 g/day.

Light chains are usually not detected by the urinary dipstick, which primarily senses albumin. Thus, the urine should be tested with sulfosalicylic acid (SSA, which detects all proteins) in any patient with acute or chronic renal failure, a bland urine sediment, and a negative or trace-positive dipstick. A markedly positive SSA test (as detected by the degree of turbidity when SSA is added to the urine) with a relatively negative dipstick is strongly suggestive of the presence of non-albumin proteins, such as light chains.

This topic provides a review of the pathogenesis and diagnosis of myeloma cast nephropathy. Overviews of the renal diseases associated with multiple myeloma and the therapy of acute renal failure in multiple myeloma are discussed separately. (See "Types of renal disease in multiple myeloma" and "Pathogenesis of immunoglobulin light chain (AL) amyloidosis and light and heavy chain deposition diseases" and "Treatment of kidney disease in multiple myeloma".)

PATHOGENESIS

Cast nephropathy occurs in the presence of excess free light chains in the plasma and urine. Cast nephropathy is rare in patients with low serum free light chain concentrations [3]. On the other hand, renal impairment is 24- to 27-fold higher in patients with high urinary immunoglobulin light chain excretion especially patients with >12 g/g creatinine [4]. The mechanism by which urinary light chains lead to renal failure is incompletely understood. Two factors are likely to be of primary importance: intratubular cast formation and direct tubular toxicity [2]. Light chains can precipitate in the tubules as a result of binding with Tamm-Horsfall mucoprotein (THMP, also called uromodulin), which is a protein of uncertain function that is normally secreted by cells of the thick ascending limb of the loop of Henle and that constitutes the matrix of all urinary casts [5,6]. The binding and precipitation leads to the formation of obstructing, dense, intratubular casts in the distal and collecting tubules that may initiate a giant cell reaction (picture 1A-C) [5-8]. The obstructing casts cause tubular rupture which allows extravasation of monoclonal light chain into the interstitium. Studies found that monoclonal immunoglobulin light chains are capable of activating nuclear factor-κB (NFκB) via Src kinases particularly c-Src [9]. The inflammation seen in myeloma cast nephropathy is the result of activation of chemokines such as monocyte chemotactic protein-1 (MCP-1) via this mechanism. (See "Chapter 4D: Tamm-Horsfall mucoprotein".)

An important contributor to cast nephropathy is volume depletion, which may promote cast formation by slowing flow within the tubules and by promoting the formation of large aggregates [2,5,10]. Other factors that have been postulated to promote intratubular cast formation include: